Method for making a transdermal fentanyl patch with even drug crystal distribution

ABSTRACT

Methods of producing a transdermal delivery patches are described comprising the preparation of a uniform suspension of drug particles. A plasticizer is added to the suspension. A solution of an adhesive is add to the suspension to form a drug suspension in the adhesive mixture. The drug suspension is coated on a release liner and all solvents are evaporated to form a solid drug reservoir layer. A medical device for transdermal administration of a drug can include the solid drug reservoir layer. Suitable drugs include fentanyl and sufentanil.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention relates to a transdermal fentanyl patch with evendrug crystal distribution.

Description of Related Art

A conventional transdermal delivery patch has been described in U.S.Pat. No. 7,247,315. The patch includes a solid drug reservoir medicaldevice for transdermal administration of a drug. The medical device hasfour layers, from top to bottom, a backing, a solid drug reservoir, arate-controlling membrane, and an adhesive layer. The adhesive layer iscovered with a release liner. The physical structure of this device issimilar to a liquid reservoir fentanyl patch as described in U.S. Pat.No. 4,588,580. The main difference in structure between the solidreservoir patch and the fentanyl patch described in U.S. Pat. No.4,588,580 is that the reservoir layer of the original fentanyl patch wasprimarily liquid in composition, while the reservoir of U.S. Pat. No.7,247,315 is a solid adhesive material. The liquid reservoir of thefentanyl patch described in U.S. Pat. No. 4,588,580 is containedphysically within the patch by a peripheral seal around the edge of thepatch, joining the backing to the rate-controlling membrane at theedges, sealing the liquid reservoir between the backing and therate-controlling membrane. No peripheral seal is needed for the solidreservoir patch described in U.S. Pat. No. 7,247,315.

The process for manufacturing the device of U.S. Pat. No. 7,247,315includes a step for manufacturing the solid drug reservoir by which theactive ingredient, fentanyl base, was present in solution with theadhesive in the coating composition that was used to produce the solidadhesive reservoir. The drug/adhesive solution was applied to asubstrate and passed through an oven to evaporate the solvent. Afterthis coated drug adhesive composition exited the coating oven, with lowlevels of residual solvent after evaporation, the drug recrystallizedwithin the solid drug reservoir. The resulting composition containedrecrystallized drug in a form that was not well-defined when viewedmicroscopically. The drug particles were small and formed agglomerates.Although the amount of drug in any specified area was controlled at thescale of the smallest dosage of the product, the size and distributionof the drug particles within the patch appeared non-uniform when viewedmicroscopically, due to the formation of agglomerates. The agglomerationof the drug particles makes it difficult to characterize accurately thesize of the drug particles within the patch. The fentanyl patchdescribed in U.S. Pat. No. 4,588,580 has high variation in the size ofthe individual drug particles and high variation in the physicaldistribution of the drug particles within the liquid reservoir asdemonstrated by the photomicrograph.

Development Principles for passive transdermal systems have beenpublished in AAPS PharmSciTech (DOI: 10.1208/s12249-011-9740-9) whichcite a requirement to test particle size of drug for evidence ofparticle size alteration. Criteria for the testing include appearance ofparticles and changes in particle form, size, shape, habit, oraggregation that may occur during the course of product processing andstorage. This testing is difficult to perform when the product ismanufactured by the process described in U.S. Pat. No. 7,247,315. Amethod is described for producing the solid drug reservoir layer in U.S.Pat. No. 7,247,315, hereby incorporated by reference into thisapplication. The drug is dispersed in isopropanol (IPA). A dimethicone,such as Medical Fluid, is added and mixed. Silicone adhesive in heptaneis then added, and the mixture is stirred until clear, thereby assuringthe drug is dissolved in this mixture.

It is desirable to provide a fentanyl patch having a compositionincluding a drug-containing layer of the patch manufactured in a mannerso that the appearance of drug particles in the product is controlledand the drug particles can be characterized according the DevelopmentPrinciples for passive transdermal systems.

SUMMARY OF THE INVENTION

The present invention provides a method of manufacture for a compositionsuitable for use in a medical device that does not include a processstep by which complete dissolution of the drug occurs.

The method of manufacture for a composition suitable for use in amedical device of the present invention includes the step of producing asolid drug reservoir layer for use in the medical device. By the methodof the present invention, the drug is first dispersed in a solvent in aratio of about 2:1 or 3:1 For example, the drug can be dispersed inheptane, at a ratio of about 2:1 or 3:1 heptane:drug w/w. This mixtureis stirred to blend the drug uniformly in the dispersion with heptane. Asuitable drug is fentanyl. Fentanyl has a finite solubility in heptane.This suspension is added quantitatively to an adhesive solution. In oneembodiment, after mixing of the dispersion for a suitable time, adimethicone, such as Medical Fluid, can be added to the dispersion, andthe dispersion. An analysis of heptane from a sample of this mixtureafter the undissolved drug is separated by filtration provides a measureof the amount of the fentanyl that has dissolved in the heptane. In theadhesive mixture of the present invention, there is no IPA present inthe mixture. The drug is suspended in the adhesive mixture rather thandissolved. The drug adhesive solution mixture is then coated on abacking layer, forming a drug reservoir layer after evaporation of thesolvent. By this process, crystalline drug is present within the drugreservoir layer immediately after the coating process.

The medical device produced by the method of the present invention isfor transdermal administration of a drug through an area of human skinduring an administration period.

In the present invention, the drug may be micronized prior to suspensionin the heptane. In this manner, the particle size of the drug in theproduct may be controlled through control of particle size of the rawmaterial active pharmaceutical ingredient (API) input to the process inthe suspension with heptane. The drug particles in the finished productare not larger than the initial particle size of the drug as it issuspended in the heptane.

By the process of the present invention the drug does not re-crystallizein the drug adhesive after coating. The crystalline drug particles inthe drug adhesive remain in the same form and remain crystallinethroughout the entire process.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic illustration of a solid reservoir transdermal drugdelivery device of the present invention.

DETAILED DESCRIPTION

The present invention relates to a drug containing composition that canbe manufactured in a manner that provides control of the particle sizeof the drug in the finished product through control of the particle sizeof the active pharmaceutical ingredient (API) input to the process. Theprocess of the present invention results in a very even distribution ofthe drug particles in a solid drug adhesive layer as viewed and measuredby microscopy. This improved process allows characterization of theappearance of drug particles, changes in particle form, size, shape,habit, or aggregation that may occur during the course of productprocessing and storage, as specified in Development Principles in AAPSPharmSciTech (DOI: 10.1208/s12249-011-9740-9).

A preferred method for preparing the drug-containing compositions of thepresent invention comprises micronizing a raw material activepharmaceutical ingredient (API) to a specified particlesize/distribution. The raw material active pharmaceutical ingredient(API) can be fentanyl and analgesically effective derivatives thereof asthe drug, it should be understood that other drugs are also suitable foruse with the teachings of the present invention including: sufentaniloxymorphone, oxycodone, hydromorphone, morphine, buprenorphine andanalgesically effective derivatives thereof.

The particle size is selected based on several criteria. First, theparticle size/distribution should be small so that the finished productcontains particles with high specific surface area so that dissolutionfrom drug particles does not limit the rate of drug release from thefinished product. Second, the drug particles should be small enough sothat all particles pass easily through all apertures present in themanufacturing process, such as the gap in the coating die. Third, thedrug particles should be small enough so that any tendency for settlingof drug particles in suspension is minimized. Finally, the drugparticles should not be so small that there is difficulty in transfer ofthe raw material to the suspension (no aerosolization). The particlesize distribution should be chosen so that no particles are greater insize than about 40 microns and the D(90) particle size distribution isgreater than about 3 microns.

An adhesive is received in a solution with a solvent to form an adhesivesolution. For example, the solvent can be heptane. Alternatively, theadhesive and solvent can be received separately, and dissolution of theadhesive in the solvent will be an additional step in the process.Example adhesives include amine resistant silicone adhesive. Examples ofsuitable amine resistant silicone adhesive matrix material compositionsinclude any type of “high tack” polydimethylsiloxane with an averagemolecular weight of between 100,000 and 5,000,000, preferably 500,000and 1,500,000.

The micronized fentanyl or sufentanil is added to a quantity of solvent,for example heptane. The micronized fentanyl or sufentanil is firstdispersed in a solvent in a ratio of about 2:1 or 3:1. For example, themicronized fentanyl or sufentanil can be dispersed in heptane, at aratio of about 2:1 or 3:1 heptane:fentanyl or heptane:sufentanil w/w.This mixture is stirred to blend the fentanyl or sufentanil uniformly inthe dispersion with heptane to create uniform suspension of the fentanylor sufentanil in the solvent. The dispersion of fentanyl or sufentanilin dispersion is quantitatively added to the adhesive solution totransfer substantially all of the fentanyl and sufentanil in dispersionto the adhesive solution.

A quantity of plasticizer can be added to the suspension, at the properratio, so that when the solvent is removed by evaporation theplasticizer will be present in the dried adhesive at the correctconcentration. Particularly preferred plasticizers include low molecularweight polydimethylsiloxane described in the National Formulary asDimethicone with a viscosity of between 20 and 12,500 centistoke, andpreferably between 300 and 400 centistoke. The solvent should beselected so that the fentanyl or sufentanil particles become suspendedin the solvent; and, when the suspension of fentanyl in the solvent withplasticizer is added to the adhesive solution, the drug particles remainsuspended without dissolving and the adhesive remains dissolved.

The dispersion of fentanyl or sufentanil in solvent and plasticizer isthen mixed with the adhesive solution. Suspended drug particles arevisible in this mixture. Because the drug is dispersed rather thandissolved in this mixture, it is necessary to assure the drug isuniformly distributed in the mixture during the subsequent processingstep (coating) in which the mixture is metered through a casting die,deposited on a moving web, and passed through an oven to evaporate thesolvent. Mixing of this mixture can continue during this coating step.

The medical device produced by the method of the present invention isfor transdermal administration of a drug through an area of human skinduring an administration period. The medical device comprising:

a solid drug reservoir layer having a top side and a bottom side and anexternal edge, wherein the solid drug reservoir layer is a compositionformed by the method of the present invention;

a rate-controlling membrane having a top and a bottom side, wherein thetop side of the rate-controlling membrane is contiguously disposed withrespect to the bottom side of the solid drug reservoir layer; and

an adhesive layer having a top and a bottom side, wherein the top sideof the adhesive layer is contiguously disposed with respect to thebottom side of the rate-controlling membrane.

In some embodiments, the present invention provides a multilaminatemedical device. Referring to FIG. 1, a schematic illustration of amultilaminate transdermal drug delivery device 100 embodiment of thepresent invention comprises a backing layer 110, a drug reservoir layer120, a rate controlling membrane 130, an adhesive layer 140 and astrippable release liner 150. The backing layer 110 can be any backinglayer described above, such as a 1-5 mil thick multilaminate comprisingPET and EVA. In some embodiments, the backing layer 110 can beimpermeable to liquids from outside medical device. The solid drugreservoir layer 120 comprises a matrix material such as an amineresistant silicone adhesive and a fentanyl flux rate lowering amount ofone or more suitable plasticizer(s) such as polydimethylsiloxane (e.g.,Medical Fluid 360 from Dow Corning). The solid drug reservoircomposition also has a dissolved and suspended drug within the soliddrug reservoir layer 120. Preferably, the drug composition is fentanyl,a fentanyl derivative, or a pharmaceutically acceptable salt thereof.The peripheral edge 122 of the solid drug reservoir layer 120 isunsealed, and can be exposed to air, in the medical device product ofthe invention shown in FIG. 1. The rate controlling membrane 130comprises low density polyethylene, polyethylene-(vinyl acetate)copolymers (with up to 40% vinyl acetate, preferably between 5 and 19%vinyl acetate, and most preferably 19% vinyl acetate). The thickness ofthe rate controlling membrane 130 can be adjusted with the 20 percentvinyl acetate in the composition to provide a selected fentanyl fluxrate, as discussed above. The rate controlling membrane 130 is betweenabout 0.5 to 5.0 mils (that is, about 0.0127 to 0.1270 inches) thick.The adhesive layer 140 is comprised of the same matrix materialcomposition and a similar type of flux rate lowering plasticizer as thesolid drug reservoir composition 120. The adhesive layer 140 comprises aflux rate lowering effective amount of the plasticizer(s) present in thesolid drug reservoir layer 120. Most preferably, the adhesive layer 140comprises the same plasticizer(s) present in the solid drug reservoirlayer 120 in approximately the same weight percentage(s). The strippablerelease liner 150 can be any release liner described above, such as a 3mil thick fluorocarbon diacrylate or silicone (polysiloxane) coatedpolyester film. The various layers are laminated or otherwise assembledinto a transdermal drug delivery device, such as a bandage or patch,having a medically appropriate predetermined size and shape as known inthe art. While FIG. 1 describes a preferred embodiment, it should berecognized that one or more of the layers may be deleted or repeated,the basic transdermal system being a drug containing matrix materialcomprising the fentanyl flux rate lowering composition of the inventionprovided and maintained in drug transferring effective relationship withthe skin. In particularly preferred embodiments comprising both anadhesive layer 140 and a solid drug reservoir layer 120, both layerspreferably comprise matrix materials and plasticizer(s) that are similarin type and amount.

A monolith medical device for trans dermal drug delivery comprises abacking layer, a drug reservoir adhesive layer and a strippable releaseliner. The backing layer can be any backing layer described above, suchas a 1-5 mils thick multi laminate comprising PET and EVA. In someembodiments, the backing layer can be impermeable to liquids fromoutside medical device. The drug reservoir adhesive layer comprises amatrix material such as an amine resistant silicone adhesive and afentanyl flux rate lowering amount of one or more suitableplasticizer(s) such as a polydimethylsiloxane emulsion (e.g., MedicalFluid 360 from Dow Corning). For example, the drug reservoir adhesivelayer can comprise about 70-95% w/w of a polysiloxane-based adhesivematrix material, about 4-20% w/w polydimethylsiloxane-type plasticizerand about 2-15% w/w of the fentanyl drug composition. The drug reservoiradhesive layer in a monolith medical device can serve as both a soliddrug reservoir and as an adhesive layer to maintain the monolith medicaldevice in transdermal drug flux permitting contact with a subject's skinthroughout an administration period. The drug reservoir adhesive layercomposition has a dissolved and suspended drug within the drug reservoiradhesive layer. Preferably, the drug composition is fentanyl, a fentanylderivative, or a pharmaceutically acceptable salt thereof. Theperipheral edge of the drug reservoir adhesive layer is unsealed, andcan be exposed to air.

The product manufactured by the present invention has the followingattributes:

1) the appearance of drug particles in the product is controlled, andthe drug particles can be characterized according the DevelopmentPrinciples described in AAPS PharmSciTech (DOI:10.1208/s12249-011-9740-9), hereby incorporated by reference in itsentirety into this disclosure.

2) the drug particles in the product are small and evenly distributed inthe product in comparison to other fentanyl patches.

3) the drug particles are present in the solid drug reservoir layer ofthe patch and not in the second adhesive layer, the skin adhesive, belowthe rate-controlling membrane

4) the crystalline form of the drug particles in the product is the sameas the crystalline form of the raw material API input to the process.

It is to be understood that the above-described embodiments areillustrative of only a few of the many possible specific embodiments,which can represent applications of the principles of the invention.Numerous and varied other arrangements can be readily devised inaccordance with these principles by those skilled in the art withoutdeparting from the spirit and scope of the invention.

1. A method for making a medical device for transdermal administrationof a drug, the method comprising the steps of: a. dispersing the drug ina first solvent to form a uniform suspension of particles of the drug;b. forming an adhesive solution of an adhesive and a second solvent; andc. adding the uniform suspension quantitatively to the adhesive solutionto add substantially all of the drug from the uniform suspension to theadhesive solution.
 2. The method of claim 1 wherein a first plasticizeris added to the suspension before it is combined with the adhesivesolution.
 3. The method of claim 1 wherein the drug is fentanyl orsufentanil.
 4. The method of claim 2 wherein before step a. the drug ismicronized so that the particle size is less than about 40 microns. 5.The method of claim 3 wherein the D(90) particle distribution is greaterthan about three microns.
 6. The method of claim 1 wherein the firstsolvent is heptane and the drug is added in a ratio of about 2:1 or 3:1of the heptane to the drug w/w.
 7. The method of claim 2 wherein thefirst plasticizer is polydimethylsiloxane matrix material.
 8. The methodof claim 1 wherein the adhesive is silicone and the second solvent isheptane.
 9. The method of claim 1 further comprising the steps ofcoating the drug suspension in the adhesive mixture on a release linerand evaporating the first and second solvent to form solid drugreservoir on the release liner.
 10. A medical device for transdermaladministration of a drug comprising: a solid drug reservoir layer formedby the steps of: a. dispersing fentanyl in a first solvent to form auniform suspension of particles of fentanyl, the first solvent isheptane; b. adding a first plasticizer to the uniform suspension ofparticles of fentanyl; c. forming an adhesive solution of an adhesiveand a second solvent; and d. adding the uniform suspension of particlesof fentanyl quantitatively to the adhesive solution to add the particlesof fentanyl from the uniform suspension to the adhesive solution,wherein when the suspension of particles of fentanyl in the heptane withthe plasticizer is added to the adhesive solution, the fentanylparticles remain suspended without dissolving.
 11. (canceled) 12.(canceled)
 13. The medical device of claim 10 wherein before step a. thefentanyl is micronized so that the particle size is less than about 40microns.
 14. The medical device of claim 10 wherein the D(90) particledistribution is greater than about three microns.
 15. The medical deviceof claim 10 wherein the fentanyl is added in a ratio of about 2:1 or 3:1of the heptane to the fentanyl w/w.
 16. The medical device of claim 10wherein the first plasticizer is polydimethylsiloxane matrix material.17. The medical device of claim 10 wherein the adhesive is silicone andthe second solvent is heptane.
 18. The medical device of claim 10wherein the suspension of particles of fentanyl in the adhesive mixtureis coated on a release liner and the first and second solvent areevaporated to form the solid drug reservoir on the release liner. 19.The medical device of claim 10 further comprising: a rate-controllingmembrane having a top and a bottom side, wherein the top side of therate-controlling membrane is contiguously disposed with respect to thebottom side of the solid drug reservoir layer; and an adhesive layerhaving a top and a bottom side, wherein the top side of the adhesivelayer is contiguously disposed with respect to the bottom side of therate-controlling membrane.
 20. The medical device of claim 10 whereinthe fentanyl comprises 2-15% w/w of a composition of the solid drugreservoir layer.
 21. The medical device of claim 10 wherein the firstplasticizer is a polydimethylsiloxane-type plasticizer and comprises4-20% w/w of a composition of the solid drug reservoir layer.
 22. Themedical device of claim 10 where in the adhesive is a polysiloxane-basedadhesive matrix material and comprises about 70-95% of the solid drugreservoir layer.